title: The mTORC2 component rictor contributes to cisplatin resistance in human ovarian cancer cells.
abstract: Resistance to cisplatin-based therapy is a major cause of treatment failure in human ovarian cancer. A better understanding of the mechanisms of cisplatin resistance will offer new insights for novel therapeutic strategies for this deadly disease. Akt and p53 are determinants of cisplatin sensitivity. Rictor is a component of mTOR protein kinase complex 2, which is required for Akt phosphorylation (Ser473) and full activation. However, the precise role of rictor and the relationship between rictor and p53 in cisplatin resistance remains poorly understood. Here, using sensitive wild-type p53 (OV2008 and A2780s), resistant wild-type p53 (C13* and OVCAR433), and p53 compromised (A2780cp, OCC1, and SKOV-3) ovarian cancer cells, we have demonstrated that (i) rictor is a determinant of cisplatin resistance in chemosensitive human ovarian cancer cells; (ii) cisplatin down-regulates rictor content by caspase-3 cleavage and proteasomal degradation; (iii) rictor down-regulation sensitizes chemo-resistant ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner; (iv) rictor suppresses cisplatin-induced apoptosis and confers resistance by activating and stabilizing Akt. These findings extend current knowledge on the molecular and cellular basis of cisplatin resistance and provide a rationale basis for rictor as a potential therapeutic target for chemoresistant ovarian cancer.
authors.affiliation: World Class University Biomodulation Major, Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Akechai
authors.initials: A
authors.lastname: Im-aram
authors.forename: Lee
authors.initials: L
authors.lastname: Farrand
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Bae
authors.forename: Gwonhwa
authors.initials: G
authors.lastname: Song
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Song
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Han
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
mesh_terms: D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; C492571:RICTOR protein, human; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D002945:Cisplatin